Genetic Evaluation for Monogenic Disorders of Low Bone Mass and Increased Bone Fragility: What Clinicians Need to Know.

PURPOSE OF REVIEW: The purpose of this review is to outline the principles of clinical genetic testing and to provide practical guidance to clinicians in navigating genetic testing for patients with suspected monogenic forms of osteoporosis. RECENT FINDINGS: Heritability assessments and genome-wide association studies have clearly shown the significant contributions of genetic variations to the pathogenesis of osteoporosis. Currently, over 50 monogenic disorders that present primarily with low bone mass and increased risk of fractures have been described. The widespread availability of clinical genetic testing offers a valuable opportunity to correctly diagnose individuals with monogenic forms of osteoporosis, thus instituting appropriate surveillance and treatment. Clinical genetic testing may identify the appropriate diagnosis in a subset of patients with low bone mass, multiple or unusual fractures, and severe or early-onset osteoporosis, and thus clinicians should be aware of how to incorporate such testing into their clinical practices.

Remnant cholesterol is associated with hip BMD and low bone mass in young and middle-aged men: a cross-sectional study.

PURPOSE: Remnant cholesterol (RC) is a contributor to cardiovascular diseases, obesity, diabetes, and metabolic syndrome. However, the specific relationship between RC and bone metabolism remains unexplored. Therefore, we aimed to investigate the relationships of RC with hip bone mineral density (BMD) and the risk of low bone mass. METHODS: Physical examination data was collected from men aged < 60 years as part of the Kailuan Study between 2014 and 2018. The characteristics of the participants were compared between RC quartile groups. A generalized linear regression model was used to evaluate the relationship between RC and hip BMD and a logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for low bone mass. Additional analyses were performed after stratification by body mass index (BMI) (≥ or < 24 kg/m2). Sensitivity analyses were performed by excluding individuals who were taking lipid-lowering therapy or had cancer, cardiovascular diseases, or diabetes. RESULTS: Data from a total of 7,053 participants were included in the analysis. After adjustment for confounding factors, RC negatively correlated with hip BMD (ß = - 0.0079, 95% CI: - 0.0133, - 0.0025). The risk of low bone mass increased from the lowest to the highest RC quartile, with ORs of 1 (reference), 1.09 (95% CI: (0.82, 1.44), 1.35 (95%CI: 1.02, 1.77), and 1.43 (95% CI: 1.09, 1.89) for Q1, Q2, Q3, and Q4, respectively (P for trend = 0.004) in the fully adjusted model. Compared to RC < 0.80 mmol/l group, the risk of low bone mass increased 39% in RC ≥ 0.80 mmol/l group (P < 0.001). The correlation between RC and hip BMD was stronger in participants with BMI ≥ 24 kg/m2 group (ß = - 0.0159, 95% CI: - 0.0289, - 0.0029). The results of sensitivity analyses were consistent with the main results. CONCLUSION: We have identified a negative correlation between serum RC and hip BMD, and a higher RC concentration was found to be associated with a greater risk of low bone mass in young and middle-aged men.

[Comparison on Performance of Quantitative Ultrasound and Dual-Energy X-ray Absorptiometry in Evaluating Bone Health of Adults Aged 18-40 Years].

Objective To compare the consistency of quantitative ultrasound(QUS)and dual-energy X-ray absorptiometry(DXA)in measuring bone mineral density(BMD)of adults aged 18-40 years in Guangzhou and evaluate the diagnostic value of QUS for identifying low bone mass.Methods DXA was employed to measure the BMD and QUS to measure the speed of sound(SOS)in 731 participants.The Bland-Altman analysis was performed to evaluate the consistency of Z scores between SOS and BMD.With the BMD Z ≤-2.00 as the diagnostic criterion for low bone mass,the receiver operating characteristics curve of QUS was established,and the area under the curve(AUC)and the sensitivity,specificity,and correct diagnostic index for the optimal cut-off of SOS Z score were calculated.Results The results of Bland-Altman analysis showed that the mean differences in the Z scores of SOS and BMD in males and females were 1.27(-0.94 to 3.47)and 0.93(-1.33 to 3.18),respectively.The AUC of SOS Z score in the diagnosis of low bone mass in males and females was 0.734(95%CI=0.380-0.788)and 0.679(95%CI=0.625-0.732),respectively.In males,the optimal cut-off of SOS Z score for low bone mass was -0.35,with the sensitivity,specificity,and correct diagnostic index of 64.1%,68.6%,and 0.327,respectively.In females,the optimal cut-off value of SOS Z scores for low bone mass was -1.14,with the sensitivity,specificity,and correct index of 73.9%,54.8%,and 0.285,respectively.Conclusion QUS and DXA show poor consistency in the diagnosis of BMD in the adults aged 18-40 years in Guangzhou,while QUS demonstrates an acceptable value in identifying low bone mass.

Bone-loading exercises versus risedronate for the prevention of osteoporosis in postmenopausal women with low bone mass: a randomized controlled trial.

PURPOSE: This randomized controlled trial compared changes in bone mineral density (BMD) and bone turnover in postmenopausal women with low bone mass randomized to 12 months of either risedronate, exercise, or a control group. METHODS: Two hundred seventy-six women with low bone mass, within 6 years of menopause, were included in analysis. Treatment groups were 12 months of (a) calcium and vitamin D supplements (CaD) (control), (b) risedronate + CaD (risedronate), or (c) bone-loading exercises + CaD (exercise). BMD and serum markers for bone formation (Alkphase B) and resorption (Serum Ntx) were analyzed at baseline, 6, and 12 months. RESULTS: Using hierarchical linear modeling, a group by time interaction was found for BMD at the spine, indicating a greater improvement in the risedronate group compared to exercise (p ≤ .010) or control groups (p ≤ .001). At 12 months, for women prescribed risedronate, changes in BMD at the spine, hip, and femoral neck from baseline were + 1.9%, + 0.9%, and + .09%; in exercise group women, + 0.2%, + 0.5%, and - 0.4%; and in control group women, - 0.7%, + 0.5%, and - 0.5%. There were also significant differences in reductions in Alkphase B (RvsE, p < .001, RvsC, p < .001) and Serum Ntx (RvsE, p = .004, RvsC, p = .007) in risedronate women compared to exercise and control groups. For risedronate, 12-month changes in Alkphase B and Serum Ntx were - 20.3% and - 19.0%; for exercise, - 6.7% and - 7.0%; and for control, - 6.3% and - 9.0%. CONCLUSION: Postmenopausal women with low bone mass should obtain adequate calcium and vitamin D and participate in bone-loading exercises. Additional use of BPs will increase BMD, especially at the spine.

A pilot screening study for low bone mass in Singaporean women using years since menopause and BMI.

OBJECTIVE: Current risk assessment tools for osteoporosis have inconsistent performance across different cohorts, making them difficult for clinical practice. This study aimed to evaluate a simple screening index comprising years since menopause (YSM) and body mass index (BMI) that identifies postmenopausal Singaporean women with a greater likelihood of low bone mass. METHODS: The study used data from 188 treatment-naïve postmenopausal women. The associations between low bone mass and different demographic variables, including age, YSM and BMI, were assessed using multivariable logistic regression. Diagnostic performance of the calculated screening index was compared to the Osteoporosis Self-Assessment Tool for Asians (OSTA) and the Fracture Risk Assessment Tool (FRAX®). RESULTS: YSM and BMI were significantly associated with low bone mass. The area under the receiver operating characteristic curves was 0.803 for the screening index, 0.759 for the OSTA, 0.683 for the FRAX® (major osteoporotic fracture probability [MOFP]) and 0.647 for the FRAX® (hip fracture probability [HFP]). Non-parametric Spearman's correlation between the screening index and the other models was 0.857 with the OSTA score, 0.694 with the FRAX® (HFP) and 0.565 with the FRAX® (MOFP) (p < 0.0005). CONCLUSIONS: The diagnostic performance of the screening index comprising YSM and BMI was equivalent to the OSTA and the FRAX®. A risk chart was developed for clinicians to identify and recommend subjects for a further dual-energy X-ray absorptiometry scan. Validation of this model in larger and more diverse cohorts is required.

Is CONUT score a predictor of morbidity in patients with adult transfusion dependent beta thalassemia?

OBJECTIVE: Increased life span with regular transfusion and iron chelator treatments enhances the importance of nutrition in beta thalassemia. Controlling Nutritional Status (CONUT) score is a nutritional index calculated on serum albumin, total cholesterol and lymphocyte count. We aim to evaluate need for transfusion and the clinical conditions which cause morbidity with CONUT score in patients with adult transfusion dependent beta thalassemia (BTD). METHOD: We conducted a retrospective study at the Denizli Thalassemia Center. We used Mann Whitney Utest for comparing. We applied logistic regression analysis and ROC analysis to evaluate CONUT score and clinical effects. RESULTS: A total of 102 patients with BTD were included. 89 were beta thalassemia major and 13 were transfusion dependent thalassemia intermedia (44 male,58 female). The median age was 26. The mean follow up period was 26 months. The median of CONUT score was 3.0 (min: 0-max: 6). CONUT score of 54 patients (52.9%) was high (≥3). We found significant difference with CONUT score ≥3 (median:32 units) and CONUT score of <3 (median:26.5 units) in terms of annual erythrocyte transfusion amount (p = 0.001). Low bone mass, vitamin D deficiency / insufficiency and hypogonadism were found to be more common with high CONUT score (≥3) (p = 0.001). CONUT score is a distinguishing parameter for hypogonadism (p = 0.001; AUC = 0.922) and low bone mass (p = 0.001; AUC = 0.867). CONCLUSION: CONUT score can be used as a predictor to evaluate need for transfusion and morbidity of patients with BTD. If nutritional status is closely followed with CONUT score and nutritional deficiency is corrected, cost and complications will be decreased and expanctancy of life can be increased.

OPG-Fc treatment partially rescues low bone mass phenotype in mature Bgn/Fmod deficient mice but is deleterious to the young mouse skeleton.

Biglycan (Bgn) and Fibromodulin (Fmod) are small leucine rich proteoglycans (SLRPs) which are abundant in the extra-cellular matrix (ECM) of mineralized tissues. We have previously generated a Bgn/Fmod double knock-out (DKO) mouse model and found it has a 3-fold increase in osteoclastogenesis compared with Wild type (WT) controls, resulting in a markedly low bone mass (LBM) phenotype. To try and rescue/repair the LBM phenotype of Bgn/Fmod DKO mice by suppressing osteoclast formation and activity, 3- and 26-week-old Bgn/Fmod DKO mice and age/gender matched WT controls were treated with OPG-Fc for 6 weeks after which bone parameters were evaluated using DEXA, micro-computed tomography (µCT) and serum biomarkers analyses. In the appendicular skeleton, OPG-Fc treatment improved some morphometric and geometric parameters in both the trabecular and cortical compartments in Bgn/Fmod DKO female and male mice, especially in the repair module. For many of the skeletal parameters analyzed, the Bgn/Fmod DKO mice were more responsive to the treatment than their WT controls. In addition, we found that OPG-Fc treatment was not able to prevent or ameliorate the formation of ectopic ossification, which are common lesions seen in aged joints and are one of the phenotypical hallmarks of our Bgn/Fmod DKO model. Analysis of skull bones, specifically the occipital bone, showed the treatment recovered some parameters of LBM phenotype in the craniofacial skeleton, more so in the younger rescue module. Using OPG-Fc as treatment alleviated, yet did not completely restore, the severe osteopenia and mineralized tissue structural abnormalities that Bgn/Fmod DKO mice suffer from.

Deep Learning With Electronic Health Records for Short-Term Fracture Risk Identification: Crystal Bone Algorithm Development and Validation.

BACKGROUND: Fractures as a result of osteoporosis and low bone mass are common and give rise to significant clinical, personal, and economic burden. Even after a fracture occurs, high fracture risk remains widely underdiagnosed and undertreated. Common fracture risk assessment tools utilize a subset of clinical risk factors for prediction, and often require manual data entry. Furthermore, these tools predict risk over the long term and do not explicitly provide short-term risk estimates necessary to identify patients likely to experience a fracture in the next 1-2 years. OBJECTIVE: The goal of this study was to develop and evaluate an algorithm for the identification of patients at risk of fracture in a subsequent 1- to 2-year period. In order to address the aforementioned limitations of current prediction tools, this approach focused on a short-term timeframe, automated data entry, and the use of longitudinal data to inform the predictions. METHODS: Using retrospective electronic health record data from over 1,000,000 patients, we developed Crystal Bone, an algorithm that applies machine learning techniques from natural language processing to the temporal nature of patient histories to generate short-term fracture risk predictions. Similar to how language models predict the next word in a given sentence or the topic of a document, Crystal Bone predicts whether a patient's future trajectory might contain a fracture event, or whether the signature of the patient's journey is similar to that of a typical future fracture patient. A holdout set with 192,590 patients was used to validate accuracy. Experimental baseline models and human-level performance were used for comparison. RESULTS: The model accurately predicted 1- to 2-year fracture risk for patients aged over 50 years (area under the receiver operating characteristics curve [AUROC] 0.81). These algorithms outperformed the experimental baselines (AUROC 0.67) and showed meaningful improvements when compared to retrospective approximation of human-level performance by correctly identifying 9649 of 13,765 (70%) at-risk patients who did not receive any preventative bone-health-related medical interventions from their physicians. CONCLUSIONS: These findings indicate that it is possible to use a patient's unique medical history as it changes over time to predict the risk of short-term fracture. Validating and applying such a tool within the health care system could enable automated and widespread prediction of this risk and may help with identification of patients at very high risk of fracture.

A novel dominant COL11A1 mutation in a child with Stickler syndrome type II is associated with recurrent fractures.

This case describes a child with blindness, recurrent low-impact fractures, low bone mass, and intermittent joint pain who was found to have a novel missense mutation in COL11A1, consistent with Stickler syndrome type II. The case illustrates the phenotypic variability of the syndrome, which may include increased fragility in childhood. INTRODUCTION: Stickler syndrome type II is an autosomal dominant disorder caused by mutations in the gene that encodes the type XI collagen chain α1 (COL11A1). Manifestations include craniofacial dysmorphology and ocular abnormalities that may lead to blindness, hearing loss, and skeletal anomalies that range from joint pain and arthritis to scoliosis and hypermobility. METHODS: Herein, we describe a child who carried the presumed diagnosis of osteoporosis-pseudoglioma syndrome because of the combined findings of recurrent low-impact fractures due to low bone mass and blindness. The child also suffered from joint pain but had no facial dysmorphism or hearing loss. RESULTS: Targeted sequencing and deletion analysis of the LRP5, COL1A1, and COL1A2 genes failed to identify any mutations, and whole exome sequence analysis revealed a novel missense mutation (c.3032C>A:p.P1011Q) in COL11A1, consistent with Stickler type II. CONCLUSION: This case highlights the phenotypic variability of Stickler type II, broadens the list of differential diagnosis of increased bone fragility in childhood, and highlights utility of unbiased genetic testing towards establishing the correct diagnosis in children with frequent fractures.

Fractures frequently occur in older cancer patients: the MD Anderson Cancer Center experience.

PURPOSE AND INTRODUCTION: A growing number of cancer patients are older adults aged 65 years and older. Patients with cancer are at increased risk for developing osteoporosis, falls, and fractures. We sought to identify the incidence of fractures in older adults who underwent cancer care between January 2013 and December 2015. METHODS: A comprehensive geriatric assessment was performed, and bone densitometry was measured at baseline, with a 2-year follow-up. RESULTS: In this study, among 304 patients with gastrointestinal, urologic, breast, lung, and gynecologic cancers we evaluated, and who completed the bone density testing (n = 199), 80% had osteoporosis or low bone mass (osteopenia). There was a higher prevalence of osteoporosis in cancer patients (40 vs. 16%, p = 0.05) than in population studies. Vitamin D insufficiency (< 30 ng/ml) was identified in 49% of tested cases (n = 245). Risk factors for low bone mass or osteoporosis were advanced age (p = 0.05), malnutrition (p = 0.04), and frailty (p = 0.01). Over the following 2 years (median follow-up 18 months), there was an incidence of fractures of 110 per 1000 person-years, or 2.8 times higher than reported in individuals without cancer. Risk factors for fractures included advanced age (70-79 vs. 60-69 years, p = 0.05) and frailty (p = 0.03). CONCLUSION: Most older cancer patients studied have osteoporosis or low bone mass, resulting in an almost 3-fold increase in fracture risk as compared to epidemiologic studies. Bone health issues are commonly seen in older cancer patients, we recommend universal bone density testing. The initiation of antiresorptive treatment when findings are of osteopenia or osteoporosis will reduce the risk of fractures.

Association between low bone mass and the serum RANKL and OPG in patients with nephrolithiasis.

BACKGROUND: Nephrolithiasis is a risk factor for Osteopenia and osteoporosis. Receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) regulate bone remodeling and osteoclastogenesis. This study aimed to evaluate the relation between serum OPG, RANKL concentration, and bone mineral density (BMD) in patients with kidney stone disease. METHODS: Forty-four nephrolithiasis patients with either low bone mass or normal BMD (considered control group) were enrolled in this study. BMD was measured at lumbar spine (L1-L4) and femoral neck by dual-energy X-ray absorptiometry (DEXA). The serum OPG and RANKL were determined using the ELISA method. RESULTS: The median levels of serum OPG were significantly higher in nephrolithiasis patients with low bone mass compared to the nephrolithiasis patients with normal BMD (3.9 pmol/l versus 3.1 pmol/l; P = 0.03), respectively. Negative correlation was detected between bone densities of femoral neck and OPG in patients with nephrolithiasis (r = -.0344, P = 0.02). CONCLUSION: The present study showed that high serum fasting OPG levels may be indicative of femoral neck BMD in patients with nephrolithiasis.

Normocalcaemic primary hyperparathyroidism: a diagnostic and therapeutic algorithm.

In recent years, there has been increasing interest in understanding the implications of diagnosing normocalcaemic primary hyperparathyroidism (nPHPT). Many patients hope that nPHPT might explain some of their symptoms, but surgeons hesitate to offer treatment to patients whose calcium levels are normal but whose parathyroid hormone (PTH) levels are elevated in the absence of secondary causes of hyperparathyroidism. This potential new diagnosis is not well understood and may lead to inappropriate investigation and possible unnecessary operations. However, because a significant number of patients with nPHPT progress to hypercalcaemic primary hyperparathyroidism (PHPT), some consider nPHPT to be an early or mild form of hypercalcaemia. Rather than being an indolent disease, nPHPT was reported to be associated with systemic complications similar to 'classical' PHPT, and hence there is growing interest to understand who should be offered surgical treatment and who should be monitored. Further standardisation of diagnostic definition, associated complications, patient selection, surgical management and long-term outcomes are necessary. The recommendations outlined in this review are based on limited evidence from non-randomised cohort studies and expert opinion.

Protocol for a randomized controlled trial to compare bone-loading exercises with risedronate for preventing bone loss in osteopenic postmenopausal women.

BACKGROUND: In the United States, over 34 million American post-menopausal women have low bone mass (osteopenia) which increases their risk of osteoporosis and fractures. Calcium, vitamin D and exercise are recommended for prevention of osteoporosis, and bisphosphonates (BPs) are prescribed in women with osteoporosis. BPs may also be prescribed for women with low bone mass, but are more controversial due to the potential for adverse effects with long-term use. A bone loading exercise program (high-impact weight bearing and resistance training) promotes bone strength by preserving bone mineral density (BMD), improving bone structure, and by promoting bone formation at sites of mechanical stress. METHODS/DESIGN: The sample for this study will be 309 women with low bone mass who are within 5 years post-menopause. Subjects are stratified by exercise history (≥2 high intensity exercise sessions per week; < 2 sessions per week) and randomized to a control or one of two treatment groups: 1) calcium + vitamin D (CaD) alone (Control); 2) a BP plus CaD (Risedronate); or 3) a bone loading exercise program plus CaD (Exercise). After 12 months of treatment, changes in bone structure, BMD, and bone turnover will be compared in the 3 groups. Primary outcomes for the study are bone structure measures (Bone Strength Index [BSI] at the tibia and Hip Structural Analysis [HSA] scores). Secondary outcomes are BMD at the hip and spine and serum biomarkers of bone formation (alkaline phosphase, AlkphaseB) and resorption (Serum N-terminal telopeptide, NTx). Our central hypothesis is that improvements in bone strength will be greater in subjects randomized to the Exercise group compared to subjects in either Control or Risedronate groups. DISCUSSION: Our research aims to decrease the risk of osteoporotic fractures by improving bone strength in women with low bone mass (pre-osteoporotic) during their first 5 years' post-menopause, a time of rapid and significant bone loss. Results of this study could be used in developing a clinical management pathway for women with low bone mass at their peak period of bone loss that would involve lifestyle modifications such as exercises prior to medications such as BPs. TRIAL REGISTRATION: Clinicaltrials.gov NCT02186600 . Initial registration: 7/7/2014.

Direct effects of physical training on markers of bone metabolism and serum sclerostin concentrations in older adults with low bone mass.

BACKGROUND: Both gravitational loading and the forces generated by muscle contraction have direct effects on serum markers of bone metabolism. The object of this study was to examine the direct effects of a single session of resistance exercise or walking on biochemical markers of bone metabolism in participants with low bone mass. METHODS: A total of 150 otherwise healthy female subjects (mean age = 59.1 ± 7.1 years) diagnosed with osteoporosis or osteopenia were randomly allocated to either a resistance exercise group (RG; n = 50), walking group (WG; n = 50), or control group (CG; n = 50). Changes in bone-specific alkaline phosphatase (BALP), carboxy-terminal cross-linked telopeptide of type I collagen (CTX), and serum sclerostin concentrations were measured before and immediately after a single exercise intervention. RESULTS: There was no significant change in BALP values in any of the groups. Sclerostin levels increased in the RG and WG, and there was significant difference between the WG and CG after the exercise intervention (P < 0.01). In contrast, the changes in CTX concentrations from baseline were significant in the RG (P < 0.01) but not in the WG (P = 0.11), and there was a significant difference between resistance exercise and walking (P < 0.01). CONCLUSIONS: In participants with low bone mass, resistance exercise influenced the serum concentrations of CTX, a marker of bone resorption, but walking did not. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16329455 ; retrospectively registered on 05/05/2016.

Serum bicarbonate and bone mineral density in US adults.

BACKGROUND: Chronic metabolic acidosis leads to bone mineral loss and results in lower bone mineral density (BMD), which is a risk factor for osteoporosis-related fractures. The effect of low-level metabolic acidosis on bone density in the general population is unknown. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 9,724 nationally representative adults 20 years or older in NHANES (National Health and Nutrition Examination Survey) 1999-2004. FACTOR: Serum bicarbonate level. OUTCOMES: Lumbar and total BMD, as well as low lumbar and total bone mass, defined as 1.0 SD below the sex-specific mean value of young adults. MEASUREMENTS: BMD was measured by dual-energy x-ray absorptiometry and serum bicarbonate was measured in all participants. RESULTS: Both men and women with lower serum bicarbonate levels were more likely to be current smokers and had higher body mass index and estimated net endogenous acid production. There was a significant linear trend across quartiles of serum bicarbonate with lumbar BMD in the total population, as well as in sex-specific models (P=0.02 for all 3 models, P=0.1 for interaction). For total BMD, a significant association was seen with serum bicarbonate level for women but not men (P=0.02 and P=0.1, respectively; P=0.8 for interaction), and a significant association was seen for postmenopausal women but not premenopausal women (P=0.02 and P=0.2, respectively; P=0.5 for interaction). Compared with women with serum bicarbonate levels <24mEq/L, those with serum bicarbonate levels ≥27mEq/L had 0.018-g/cm(2) higher total BMD (95% CI, 0.004-0.032; P=0.01) and 31% lower odds of having low total bone mass (OR, 0.68; 95% CI, 0.46-0.99; P=0.049). LIMITATIONS: Cross-sectional study using a single measurement of serum bicarbonate. Subgroup differences are not definitive. CONCLUSIONS: Lower serum bicarbonate levels are associated with lower BMD in US adults. Further studies should examine whether serum bicarbonate levels should be incorporated into the diagnostic assessment and management of osteoporosis.

A de novo 1.58 Mb deletion, including MAP2K6 and mapping 1.28 Mb upstream to SOX9, identified in a patient with Pierre Robin sequence and osteopenia with multiple fractures.

Defects of long-range regulatory elements of dosage-sensitive genes represent an under-recognized mechanism underlying genetic diseases. Haploinsufficiency of SOX9, the gene essential for development of testes and differentiation of chondrocytes, results in campomelic dysplasia, a skeletal malformation syndrome often associated with sex reversal. Chromosomal rearrangements with breakpoints mapping up to 1.6 Mb up- and downstream to SOX9, and disrupting its distant cis-regulatory elements, have been described in patients with milder forms of campomelic dysplasia, Pierre Robin sequence, and sex reversal. We present an ∼1.58 Mb deletion mapping ∼1.28 Mb upstream to SOX9 that encompasses its putative long-range cis-regulatory element(s) and MAP2K6 in a patient with Pierre Robin sequence and osteopenia with multiple fractures. Low bone mass panel testing using massively parallel sequencing of 23 nuclear genes, including COL1A1 and COL1A2 was negative. Based on the previous mouse model of Map2k6, suggesting that Sox9 is likely a downstream target of the p38 MAPK pathway, and our previous chromosome conformation capture-on-chip (4C) data showing potential interactions between SOX9 promoter and MAP2K6, we hypothesize that deletion of MAP2K6 might have affected SOX9 expression and contributed to our patient's phenotype.

Bone mineral density, thyroid function, and gonadal status in young adult survivors of childhood cancer.

INTRODUCTION: During the last years, changes in the diagnosis and treatment have caused a significant increase of the number of young adults who experienced cancer in childhood. This enlarging population is affected by many health problems, including multiple hormone deficiencies and bone mineral deficits. This is the first polish study assessing bone mineral density and endocrine status in young adult cancer survivors. MATERIAL AND METHODS: A total of 76 long-term survivors treated for pediatric cancer were identified. The mean age at the time of study was 24.1 ±3.5 years. Bone mineral density and TSH, fT3, fT4, FSH, LH, estradiol and testosterone level were assessed for each patient. RESULTS: Nine subjects were diagnosed with subclinical hypothyroidism. We found higher level of TSH in the study group, in comparison with control group (p = 0.015). Eighteen patients had increased level of FSH. In the study group higher number of patients with high FSH level was found in comparison with the control group (p = 0.049). A low BMD was observed in 7 patients whereas mild BMD deficits were found in 19 participants. CONCLUSIONS: In conclusion, our data show that young adult cancer survivors might experienced various hormonal problems including low bone mass, thyroid impairment and gonadal dysfunction. Some of the patients required treatment, but they were not diagnosed before this study. There is the lack of proper clinical assessment among adult childhood cancer survivors in Poland. Therefore, we demonstrated the need for a comprehensive plan for longitudinal follow-up for late effects in these population.

Association of breast vascular calcifications with low bone mass in postmenopausal women.

BACKGROUND: In developing countries, there is a deficiency of densitometers with which to screen the population for osteoporosis. Thus, strategies with which to select patients for a bone density test are desirable. OBJECTIVE: To determine whether breast vascular calcifications (BVCs) may be employed to identify postmenopausal women with osteoporosis/osteopenia. METHODS: This was a cross-sectional study of postmenopausal women subjected to bilateral mammography and bone densitometry (DXA) of the spine and hip. A medical interview registered possible confounding factors, such as age, length of menopause, previous use of postmenopausal hormone therapy, family history of osteoporosis, smoking, alcoholism, hypertension, diabetes, cardiovascular diseases, and medication use. RESULTS: The study included 211 postmenopausal women aged 62.1 ± 9.3 years, 38 of whom (18.0%) exhibited BVC. Osteoporosis was detected in 36 (17.1%), and a T-score < 21.0 for any site was found in 164 (77.7%). No statistically significant difference was found between the groups without BVC (n = 173) and with BVC (n = 38) for the prevalence of 'osteoporosis' or 'moderate/severe osteopenia or osteoporosis' at the spine or at any other site. There was a difference between the groups in terms of age (59.0 ± 7.8 vs. 71.9 ± 8.9 years, respectively; p < 0.001), sedentary lifestyle (57.8% vs. 84.2%, respectively; p = 0.002), smoking (27.7% vs. 7.9%, respectively; p = 0.009), and high blood pressure (65.3% vs. 92.1%, respectively; p = 0.001). Logistic regression analysis confirmed the lack of statistical significance for BVC as a predictor of an osteoporosis diagnosis. Sensitivity values of BVCs to detect osteoporosis or osteopenia ranged from 17.9% to 25.0%. CONCLUSION: BVCs have been shown to be inadequate to identify postmenopausal women with osteoporosis or osteopenia.

Cost-minimization study comparing annual infusion of zoledronic acid or weekly oral alendronate in women with low bone mineral density.

Cost-minimization study to assess the annual direct costs of 2 antiresorptive strategies in postmenopausal women with low bone mineral densities (BMDs). Patients were randomly assigned to receive 70 mg of oral weekly alendronate or a 1-time 5mg of intravenous zoledronic acid. All medical and nonmedical direct costs were recorded for 1 yr. Student's t-test or the Chi-squared test was used. A total of 101 postmenopausal women were enrolled with a mean age of 58.3 ± 7.6 yr and a postmenopausal period of 13.5 ± 8.3 yr. A total of 50 patients completed 1 yr of alendronate and 51 patients received zoledronic acid. At baseline, no differences were seen between the 2 groups in anthropometric measures, comorbidities, and bone mineral density. The costs for medical attention for low bone mass were $81,532 (US Dollars) for the alendronate group and $69,251 for the zoledronic acid group; the cost per patient was $1631 in the alendronate group vs $1358 in the zoledronic acid group (p<0.0001). Therefore, zoledronic acid treatment provided an annual savings of 15% of the direct costs compared with oral alendronate treatment. Moreover, there was a significant increase in lumbar spine T-scores in the zoledronic acid group when compared with the alendronate group. Annual zoledronic acid infusion as an antiresorptive treatment in women with low BMD provides significant monetary savings when compared with weekly alendronate therapy for 1 yr. Zoledronic acid infusion is also linked to higher increase in BMD and compliance.

Effects of Omega-3 Polyunsaturated Fatty Acid Supplementation on Bone Turnover in Older Women.

Animal and human studies indicate that omega (n)-3 polyunsaturated fatty acids (PUFA) can influence bone health. We conducted a randomized, double-blind, placebo-controlled trial of the effects of n-3 long chain (LC) PUFA supplementation (N-3 LCPUFA) on red blood cell (RBC) fatty acid levels and bone turnover markers in older postmenopausal women. One hundred and twenty-six postmenopausal women (mean age 75±7 years) were treated with n-3 LCPUFA (1.2 g eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA]/day, n=85) or placebo (olive oil, n=41) for 6 months. All women received 315 mg calcium citrate and 1000 IU cholecalciferol. RBC DHA (weight %) increased in the n-3 LCPUFA group, compared to no change in the placebo group (P<0.001). The ratio of DHA+EPA:arachidonic acid (AA) increased by 42 % in the n-3 LCPUFA group and by 5% in the placebo group (P<0.001). Bone-specific alkaline phosphatase and osteocalcin decreased in the n-3 LCPUFA group (P<0.05) with no between-group difference. Short-term n-3 LCPUFA supplementation increased RBC concentrations of DHA and n-3:n-6 ratios. Bone turnover decreased with n-3 LCPUF, but not statistically compared to placebo. The results point to the need for investigations with greater dosages of n-3 LCPUFA for a longer duration to understand the contribution to bone metabolism in postmenopausal women.